In human beings and animals, many molecules are present in the blood and other body fluids, such as urine and saliva, and these molecules can be used as markers for different diseases or for assessing the general health status. The concentration of these molecules may vary over time in the body, from long time to short time. It is common that the concentration in such body fluids of a specific molecule changes with time due to a disease. A disease may involve a concentration change of several molecules, each with their specific time pattern. Acute myocardial infarction (AMI) is an example where several analytes (molecules) are released on different time scales, and showing different degree of specificity.
Almost all clinical decisions are made upon absolute responses, which have shown to have many limitations. In particular there is a problem in using absolute values in that they must be related to a base line, e.g. values for a healthy person. Since base lines may vary between individuals, absolute values can result in erroneous interpretations of measurements.
Coronary diseases, especially AMI, are the largest factor for human death, and there is a great demand for clinical solutions to improve the treatment for these diseases.
ECG
A very common method for determining AMI in the early phase (within 2 hours from pain onset), is to record an electrocardiogram (ECG). This is a method invented by Willem Einthoven and has been used since the early 1920's. The method involves measuring the electrical potential close to the heart at different points as a function of time for six points, denoted V1 to V6 around the chest, close to the heart. The potential changes versus time emanates from depolarization waves within the heart, emanating from the sinus point. There are three typical pulses, denoted P from auricular contraction, QRS from ventricle contraction, and T from repolarization. At AMI and other cardiac diseases where there is an ischemic (lack of blood circulation) condition there are changes in ECG pattern. However, the changes are very difficult to interpret. Even for a highly trained specialist it is in many cases impossible to determine an AMI. Typical ECG signs for an early AMI are primarily increasing level of the ST segment for the V1 to V5 connections, secondarily a decrease of amplitude and broadening of the Q-wave from V1 to V3 connections, and sometimes a negative T-wave from V2 to V6 connections. In the early phase of AMI, ECG changes are small and difficult to interpret [Jern, 1990].
Other cardiac diseases may show different patterns, e.g. heart failure may show a lower ST-segment. A lower ST-segment may be a sign of lack of oxygen in the heart.
Cardiac Markers
Clinical diagnosis of coronary syndromes have lately been characterized by cardiac markers, patent WO2004059293, and WO03016910. One of the first reliably markers for AMI was CKMB, which has lately been substituted for Troponin I and T. There are many other molecules that are more or less specific as cardiac markers, such as Myoglobin and Lactate Hydro Genase (LHD). Myoglobin is an early marker in that way that it will have peak valued in the blood after typical eight hours after pain onset (time for occlusion). However, myoglobin is present in skeleton muscle and hence not specific to cardiac damage, leading to low specificity for AMI. CKMB is more specific to cardiac damage, but is slower and will lead to a typical peak value after typical 24 hours. Troponin I and C are more specific, but show similar time to peak value. The traditional way to diagnose AMI has been to check the level of the cardiac markers at different times, typical at admission, and after 6 and 12 hours. Unfortunately the diagnosis has been set when the time window for treatment is gone. Since a long time people have measured differences in cardiac enzymes, and Bernsten et al. have taken the slope of CK-MB Clin Chem 1983 29(3) p 590-592. Collingson et al. have showed how slope measurements can be performed as a retrospective diagnosis: Clin. Chem. 1983, 29(3) p 590-592, Ann Clin Biochem, 1988 25 p 376-382, J Clin Pathol 1989, 42 p 1126-31, Ann Clin Biochem 1992, 29 p 34-47, Ann Clin Biochem 1993, 30 p 407-409. Others have done the same, not being able to perform an diagnosis for treatment: Ann Clin Biochem 1989, 26, p 558-559, Ann Clin Biochem 1991, 28 p 103-104, J Clin Pathol 1994, 47 p 995-998. These methods seems to vanish, for many reasons, e.g. the sampling time have been too long due to cost and lack of suitable equipment. The sparse values means that changes in the slopes (i.e. curvatures) will be lost. Logarithmic values have been used in slope calculations, which means that slope values are dependent on time sampling. Moreover, it lead to difficulties to set cut off values.
The markers mentioned have been used to predict the size of necrosis, where total amount released (area under curve) or maximum concentration are used. There are studies where the concentration of CK-MB in blood after an AMI is fitted to a mathematical curve R. Vollmer et al. Am J Clin Pathol, 1993 100, p 293-298. A formula used (Christenson et al) is y=a*exp[(−0.5*(ln t−b)/c)2] (correct formula is probably y=a*exp[−0.5*(ln(t/b)/c)2]), where a, b, c are parameters, and t the time. The parameter a is the amplitude, b should be the time to peak maximum, and c is a parameter defining the width. Such functions have been used to evaluate therapies, especially thrombolytic therapy, and predicting clinical outcome related to coronary conditions, in some cases by using the slope of the curve on the descending portion, Christenson et al. U.S. Pat. No. 6,662,114. The formula above has a limitation by letting the ascending and descending portions of the curve be 100% dependent of each other.
Evaluation of more than one cardiac marker has been evaluated using artificial neural networks, patent WO97/48327.
A common problem in previous techniques is the requirement of blood plasma or serum. This means that the sample are treated, which may lead to different behavior, and definitely means that the original concentration of analytes are changed. Moreover, there is likely that there will be a variation in analyte concentration due to the difficulties to perform the treatments exactly the same from tome to time.
Previous methods of measuring cardiac markers have been retrospective, in that manner that response levels and slope levels have been used to see what happened (when the damage is permanent). It is not used prospective. With prospective method, we define it as a method where signals for diagnosis is continuously presented as long as measurements are performed, and proper diagnosis and decision of treatment can continuously be made as health status evolve.
MRI and CT
There are other techniques to detect myocardial infarction, such as magnetic resonance imaging (MRI) and computer tomography (CT). These techniques require large and expensive apparatus and special trained operators, which make them unsuitable to use as a common diagnostic method.